🔗

Mappings

MONDO

MONDO:0009603 3-hydroxyisobutyryl-CoA hydrolase deficiency

◆

Subtypes

3

Neonatal onset

Least frequent subtype. Presents at birth with hypotonia, seizures, and feeding difficulties, with high risk of death in childhood; survivors develop developmental delay, poor weight gain, and a movement disorder.

Infantile onset

Most common subtype. Presents in the first two years of life with feeding difficulties, vomiting, developmental delay with regression, hypotonia, seizures, movement disorder, microcephaly, vision impairment, and episodes of neurologic deterioration.

Late onset

Second most common subtype. Presents in childhood as a slowly progressive disease with significant movement disorder with or without paroxysmal dystonia, variable cognitive impairment, and high survivability.

⚙

Pathophysiology

4

HIBCH enzyme deficiency

Biallelic HIBCH variants reduce mitochondrial 3-hydroxyisobutyryl-CoA hydrolase activity and disrupt valine degradation.

HIBCH link

valine catabolic process link ↓ DECREASED

mitochondrial matrix link

Downstream

Valine catabolic block Loss of HIBCH activity blocks valine breakdown at the mitochondrial hydrolysis step.

Show evidence (1 reference)

PMID:24299452 SUPPORT Human Clinical

"HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency."

This directly supports the initiating enzymatic defect in HIBCH deficiency.

Valine catabolic block

Loss of HIBCH activity blocks valine degradation and promotes accumulation of upstream toxic valine-derived intermediates.

valine catabolic process link ↓ DECREASED branched-chain amino acid catabolic process link ↓ DECREASED

mitochondrial matrix link

Downstream

Multiple mitochondrial dysfunction Valine catabolic impairment secondarily contributes to combined respiratory chain and pyruvate dehydrogenase dysfunction.

C4-OH acylcarnitine HIBCH-related valine catabolic impairment is associated with elevated hydroxy-C4-carnitine in dried blood spots.

Urinary 2,3-dihydroxy-2-methylbutyrate The valine catabolic block produces elevated urinary 2,3-dihydroxy-2-methylbutyrate.

Urinary S-(2-carboxypropyl)cysteamine Toxic valine-derived intermediates are reflected by elevated urinary S-(2-carboxypropyl)cysteamine.

Show evidence (1 reference)

PMID:24299452 SUPPORT Human Clinical

"Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism."

This directly supports a valine catabolic block as the biochemical basis of HIBCH deficiency.

Multiple mitochondrial dysfunction

HIBCH deficiency can produce combined mitochondrial respiratory chain enzyme deficiency and pyruvate dehydrogenase complex dysfunction.

oxidative phosphorylation link ↓ DECREASED pyruvate metabolic process link ↓ DECREASED

mitochondrion link

Downstream

Leigh-like neurodegeneration Mitochondrial energy failure and basal ganglia injury manifest as a Leigh-like neurodegenerative syndrome.

Show evidence (1 reference)

PMID:24299452 SUPPORT Human Clinical

"The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother."

This directly supports the combined mitochondrial dysfunction that can occur in HIBCH deficiency.

Leigh-like neurodegeneration

The combined energy failure produces a progressive Leigh-like neurodegenerative encephalopathy with early basal ganglia involvement.

Downstream

Global developmental delay Leigh-like neurodegeneration causes early neurodevelopmental delay.

Developmental regression Progressive mitochondrial encephalopathy can cause loss of previously acquired developmental skills.

Hypotonia Central neurodegeneration contributes to low tone.

Encephalopathy Basal ganglia and mitochondrial injury manifest as encephalopathy.

Feeding difficulties Neurodegenerative disease in infancy can impair feeding.

Vomiting Infantile-onset HIBCH deficiency can present with vomiting during the early Leigh-like neurologic disease course.

Movement disorder Progressive HIBCH deficiency can produce a movement disorder in later infancy or childhood.

Seizure Leigh-like HIBCH disease can present with seizures in neonatal and infantile-onset disease.

Dystonia Later-onset HIBCH neurodegeneration can include paroxysmal dystonia as part of the movement-disorder phenotype.

Microcephaly Infantile-onset HIBCH deficiency can include microcephaly as part of the neurodevelopmental disease spectrum.

Visual impairment Leigh-like HIBCH neurodegeneration can include visual impairment.

Cognitive impairment Late-onset HIBCH deficiency can include variable cognitive impairment.

Show evidence (2 references)

PMID:33762937 SUPPORT Human Clinical

"HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series"

This directly supports Leigh-like neurodegeneration as the downstream clinical mechanism in HIBCH deficiency.

PMID:24299452 SUPPORT Human Clinical

"Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease."

This directly links HIBCH deficiency to progressive Leigh-like neurodegeneration with basal ganglia involvement.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

12

Digestive 2

Feeding difficulties Feeding difficulties (HP:0011968)

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties."

This directly supports feeding difficulties as a core clinical feature.

Vomiting Vomiting (HP:0002013)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Infantile onset is the most common phenotype, presenting in the first two years of life with feeding difficulties, vomiting, developmental delay with regression, hypotonia, seizures, movement disorder, microcephaly, vision impairment, and episodes of neurologic deterioration."

GeneReviews documents vomiting as a feature of infantile-onset HIBCH deficiency.

Eye 1

Visual impairment Visual impairment (HP:0000505)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Infantile onset is the most common phenotype, presenting in the first two years of life with feeding difficulties, vomiting, developmental delay with regression, hypotonia, seizures, movement disorder, microcephaly, vision impairment, and episodes of neurologic deterioration."

GeneReviews documents vision impairment as a feature of infantile-onset HIBCH deficiency.

Head and Neck 1

Microcephaly Microcephaly (HP:0000252)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Infantile onset is the most common phenotype, presenting in the first two years of life with feeding difficulties, vomiting, developmental delay with regression, hypotonia, seizures, movement disorder, microcephaly, vision impairment, and episodes of neurologic deterioration."

GeneReviews documents microcephaly as a feature of infantile-onset HIBCH deficiency.

Musculoskeletal 1

Hypotonia Hypotonia (HP:0001252)

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties."

This directly supports hypotonia as a common HIBCH presentation.

Nervous System 7

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties."

This directly supports developmental delay as a prominent HIBCH phenotype.

Developmental regression Developmental regression (HP:0002376)

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties."

This directly supports developmental regression as a prominent HIBCH phenotype.

Encephalopathy Encephalopathy (HP:0001298)

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties."

This directly supports encephalopathy as part of the HIBCH phenotype.

Seizure Seizure (HP:0001250)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Neonatal onset, the least frequent phenotype, is characterized by hypotonia, seizures, and feeding difficulties at birth."

This directly supports seizures as part of the HIBCH clinical spectrum.

Movement disorder Abnormality of movement (HP:0100022)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Late onset is the second most common phenotype, presenting in childhood as a slowly progressive disease with significant movement disorder with or without paroxysmal dystonia, variable cognitive impairment, and high survivability."

This directly supports a movement disorder phenotype in the HIBCH spectrum.

Dystonia Dystonia (HP:0001332)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Late onset is the second most common phenotype, presenting in childhood as a slowly progressive disease with significant movement disorder with or without paroxysmal dystonia, variable cognitive impairment, and high survivability."

This directly supports dystonia as part of the late-onset HIBCH spectrum.

Cognitive impairment Cognitive impairment (HP:0100543)

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Late onset is the second most common phenotype, presenting in childhood as a slowly progressive disease with significant movement disorder with or without paroxysmal dystonia, variable cognitive impairment, and high survivability."

GeneReviews documents variable cognitive impairment in late-onset HIBCH deficiency.

🧬

Genetic Associations

1

HIBCH (Loss of function)

Show evidence (2 references)

PMID:24299452 SUPPORT Human Clinical

"HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency."

This directly supports HIBCH as the causal gene and explicitly names the relevant mitochondrial differential diagnosis context.

CGGV:assertion_26621ace-7c6b-4a1c-8286-02c4cb8a1544-2019-11-07T222437.403Z SUPPORT Other

ClinGen classifies the HIBCH-3-hydroxyisobutyryl-CoA hydrolase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

3

Valine-Restricted Diet

Action: dietary intervention MAXO:0000088

Dietary restriction of valine is the primary targeted therapy for HIBCH deficiency, addressing the block in valine catabolism. Special medical food formulas can be delivered orally or by gastrostomy tube, with total protein restriction as an alternative when formula adherence is poor.

Mechanism Target:

MODULATES Valine catabolic block — Valine restriction reduces dietary substrate flux into the impaired valine catabolic pathway.

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"MANAGEMENT: Targeted therapy: Valine-restricted diet."

GeneReviews identifies valine restriction as targeted therapy for the pathway-level HIBCH defect.

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"MANAGEMENT: Targeted therapy: Valine-restricted diet. As seen in other metabolic disorders, treatment using special formulas (medical food) can be implemented successfully via oral route in individuals diagnosed within the first few months of life."

GeneReviews explicitly identifies valine-restricted diet as the primary targeted therapy for HIBCH deficiency.

Supportive metabolic and dietary management

Action: supportive care MAXO:0000950

HIBCH deficiency has no established curative therapy, but reported patients have received drug and dietary management with clinical improvement in some cases.

Show evidence (1 reference)

PMID:33762937 PARTIAL Human Clinical

"We administered drug and dietary treatment. During follow-up, five patients responded positively to treatment with a significant decrease in NPMDS scores."

This supports the use of non-curative supportive metabolic management, although the paper does not specify a standardized regimen.

Agents and diets to avoid

Action: supportive care MAXO:0000950

Due to secondary mitochondrial abnormalities in HIBCH deficiency, sodium valproate should be avoided when possible and ketogenic or modified Atkins diets should be avoided because of potential side effects.

Show evidence (1 reference)

PMID:41264763 SUPPORT Human Clinical

"Agents/circumstances to avoid: Due to secondary mitochondrial abnormalities it may be beneficial to avoid sodium valproate if possible; consider anesthesia use carefully; avoid prolonged propofol use; prevent catabolism; avoid neuromuscular blocking agents in those with muscle disease; avoid..."

GeneReviews explicitly lists valproate and ketogenic or modified Atkins diets among agents and circumstances to avoid in HIBCH deficiency.

🔬

Biochemical Markers

3

C4-OH acylcarnitine (INCREASED)

Context: Elevation of hydroxy-C4-carnitine in dried blood spots is a useful biochemical clue in HIBCH deficiency.

Pathograph Readouts

Readout Of Valine catabolic block Positive Diagnostic

Elevated C4-OH acylcarnitine reports disturbed valine catabolism downstream of impaired HIBCH activity.

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"Five (5/7) patients presented with elevated C4-OH in dried blood spots, and the level was probably correlated with the NPMDS scores during the peak disease phase."

This directly supports elevated C4-OH as a recurrent biochemical marker.

Urinary 2,3-dihydroxy-2-methylbutyrate (INCREASED)

Context: Urinary 2,3-dihydroxy-2-methylbutyrate is an elevated organic acid marker in HIBCH deficiency.

Pathograph Readouts

Readout Of Valine catabolic block Positive Diagnostic

Elevated urinary 2,3-dihydroxy-2-methylbutyrate reports accumulation of valine-derived intermediates from the HIBCH catabolic block.

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients and elevated S-(2-caboxypropyl)cysteamine in urine was found in three patients (3/3)."

This directly supports urinary 2,3-dihydroxy-2-methylbutyrate as a disease-associated biochemical marker.

Urinary S-(2-carboxypropyl)cysteamine (INCREASED)

Context: Urinary S-(2-carboxypropyl)cysteamine is another disease-associated metabolite in HIBCH deficiency.

Pathograph Readouts

Readout Of Valine catabolic block Positive Diagnostic

Elevated urinary S-(2-carboxypropyl)cysteamine reports toxic valine-derived intermediate buildup in HIBCH deficiency.

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients and elevated S-(2-caboxypropyl)cysteamine in urine was found in three patients (3/3)."

This directly supports urinary S-(2-carboxypropyl)cysteamine as a disease-associated biochemical marker.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from 3-hydroxyisobutyryl-CoA hydrolase deficiency:

Leigh syndrome MONDO:0009723

Overlapping Features HIBCH deficiency is a recognized Leigh-like disorder and can be mistaken for Leigh syndrome on clinical grounds.

Show evidence (1 reference)

PMID:33762937 SUPPORT Human Clinical

"HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series"

This directly supports Leigh syndrome as an important clinical differential.

Pyruvate dehydrogenase deficiency MONDO:0019169

Overlapping Features Because HIBCH deficiency can produce pyruvate dehydrogenase complex dysfunction, primary PDH deficiency is a major differential diagnosis.

Show evidence (1 reference)

PMID:24299452 SUPPORT Human Clinical

"HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency."

This explicitly names pyruvate dehydrogenase deficiency as a key differential diagnosis.

ECHS1 deficiency Not Yet Curated MONDO:0014563

Overlapping Features ECHS1 deficiency is the key biochemical differential because ECHS1 acts immediately upstream of HIBCH in valine degradation and can present with a remarkably similar Leigh-like phenotype.

Show evidence (1 reference)

PMID:37309295 SUPPORT In Vitro

"Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA)."

This review explicitly places ECHS1 deficiency alongside HIBCH deficiency in the valine/isoleucine degradation disorders with overlapping biochemical context.

{ }

Source YAML

click to show

name: 3-hydroxyisobutyryl-CoA hydrolase deficiency
creation_date: "2026-04-15T00:00:00Z"
updated_date: "2026-05-19T17:18:26Z"
category: Mendelian
description: >-
  3-hydroxyisobutyryl-CoA hydrolase deficiency is an inborn error of valine
  catabolism caused by biallelic HIBCH variants, leading to neurodevelopmental
  impairment and a Leigh-like metabolic encephalopathy.
disease_term:
  preferred_term: 3-hydroxyisobutyryl-CoA hydrolase deficiency
  term:
    id: MONDO:0009603
    label: 3-hydroxyisobutyryl-CoA hydrolase deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009603
      label: 3-hydroxyisobutyryl-CoA hydrolase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- hereditary disease
- inborn error of metabolism
has_subtypes:
- name: Neonatal onset
  description: >-
    Least frequent subtype. Presents at birth with hypotonia, seizures, and
    feeding difficulties, with high risk of death in childhood; survivors
    develop developmental delay, poor weight gain, and a movement disorder.
- name: Infantile onset
  description: >-
    Most common subtype. Presents in the first two years of life with feeding
    difficulties, vomiting, developmental delay with regression, hypotonia,
    seizures, movement disorder, microcephaly, vision impairment, and
    episodes of neurologic deterioration.
- name: Late onset
  description: >-
    Second most common subtype. Presents in childhood as a slowly progressive
    disease with significant movement disorder with or without paroxysmal
    dystonia, variable cognitive impairment, and high survivability.
pathophysiology:
- name: HIBCH enzyme deficiency
  description: >-
    Biallelic HIBCH variants reduce mitochondrial 3-hydroxyisobutyryl-CoA
    hydrolase activity and disrupt valine degradation.
  genes:
  - preferred_term: HIBCH
    term:
      id: hgnc:4908
      label: HIBCH
  biological_processes:
  - preferred_term: valine catabolic process
    term:
      id: GO:0006574
      label: L-valine catabolic process
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HIBCH deficiency, a disorder of valine catabolism, is a novel cause of
      the multiple mitochondrial dysfunctions syndrome, and should be considered
      in the differential diagnosis of patients presenting with multiple RC
      deficiencies and/or pyruvate dehydrogenase deficiency.
    explanation: >-
      This directly supports the initiating enzymatic defect in HIBCH
      deficiency.
  downstream:
  - target: Valine catabolic block
    description: >-
      Loss of HIBCH activity blocks valine breakdown at the mitochondrial
      hydrolysis step.
    causal_link_type: DIRECT
- name: Valine catabolic block
  description: >-
    Loss of HIBCH activity blocks valine degradation and promotes accumulation
    of upstream toxic valine-derived intermediates.
  biological_processes:
  - preferred_term: valine catabolic process
    term:
      id: GO:0006574
      label: L-valine catabolic process
    modifier: DECREASED
  - preferred_term: branched-chain amino acid catabolic process
    term:
      id: GO:0009083
      label: branched-chain amino acid catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-valine
    term:
      id: CHEBI:16414
      label: L-valine
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH
      mutations is a rare cerebral organic aciduria caused by disturbance of
      valine catabolism.
    explanation: >-
      This directly supports a valine catabolic block as the biochemical basis
      of HIBCH deficiency.
  downstream:
  - target: Multiple mitochondrial dysfunction
    description: >-
      Valine catabolic impairment secondarily contributes to combined
      respiratory chain and pyruvate dehydrogenase dysfunction.
    causal_link_type: DIRECT
  - target: C4-OH acylcarnitine
    description: >-
      HIBCH-related valine catabolic impairment is associated with elevated
      hydroxy-C4-carnitine in dried blood spots.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33762937
      reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Five (5/7) patients presented with elevated C4-OH in dried blood spots,
        and the level was probably correlated with the NPMDS scores during the
        peak disease phase.
      explanation: >-
        The HIBCH cohort supports elevated C4-OH as a biochemical readout of
        the disturbed valine-catabolism state.
  - target: Urinary 2,3-dihydroxy-2-methylbutyrate
    description: >-
      The valine catabolic block produces elevated urinary
      2,3-dihydroxy-2-methylbutyrate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33762937
      reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7)
        patients and elevated S-(2-caboxypropyl)cysteamine in urine was found
        in three patients (3/3).
      explanation: >-
        The cohort directly supports urinary 2,3-dihydroxy-2-methylbutyrate as
        an elevated disease-associated metabolite.
  - target: Urinary S-(2-carboxypropyl)cysteamine
    description: >-
      Toxic valine-derived intermediates are reflected by elevated urinary
      S-(2-carboxypropyl)cysteamine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33762937
      reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7)
        patients and elevated S-(2-caboxypropyl)cysteamine in urine was found
        in three patients (3/3).
      explanation: >-
        The cohort supports urinary S-(2-carboxypropyl)cysteamine as another
        elevated metabolite in HIBCH deficiency.
- name: Multiple mitochondrial dysfunction
  description: >-
    HIBCH deficiency can produce combined mitochondrial respiratory chain
    enzyme deficiency and pyruvate dehydrogenase complex dysfunction.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  - preferred_term: pyruvate metabolic process
    term:
      id: GO:0006090
      label: pyruvate metabolic process
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index case had deficiencies of multiple RC enzymes and PDHc in
      skeletal muscle and fibroblasts respectively, but these were normal in
      his younger brother.
    explanation: >-
      This directly supports the combined mitochondrial dysfunction that can
      occur in HIBCH deficiency.
  downstream:
  - target: Leigh-like neurodegeneration
    description: >-
      Mitochondrial energy failure and basal ganglia injury manifest as a
      Leigh-like neurodegenerative syndrome.
    causal_link_type: DIRECT
- name: Leigh-like neurodegeneration
  description: >-
    The combined energy failure produces a progressive Leigh-like
    neurodegenerative encephalopathy with early basal ganglia involvement.
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series
    explanation: >-
      This directly supports Leigh-like neurodegeneration as the downstream
      clinical mechanism in HIBCH deficiency.
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease.
    explanation: >-
      This directly links HIBCH deficiency to progressive Leigh-like
      neurodegeneration with basal ganglia involvement.
  downstream:
  - target: Global developmental delay
    description: >-
      Leigh-like neurodegeneration causes early neurodevelopmental delay.
    causal_link_type: DIRECT
  - target: Developmental regression
    description: >-
      Progressive mitochondrial encephalopathy can cause loss of previously
      acquired developmental skills.
    causal_link_type: DIRECT
  - target: Hypotonia
    description: >-
      Central neurodegeneration contributes to low tone.
    causal_link_type: DIRECT
  - target: Encephalopathy
    description: >-
      Basal ganglia and mitochondrial injury manifest as encephalopathy.
    causal_link_type: DIRECT
  - target: Feeding difficulties
    description: >-
      Neurodegenerative disease in infancy can impair feeding.
    causal_link_type: DIRECT
  - target: Vomiting
    description: >-
      Infantile-onset HIBCH deficiency can present with vomiting during the
      early Leigh-like neurologic disease course.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Movement disorder
    description: >-
      Progressive HIBCH deficiency can produce a movement disorder in later
      infancy or childhood.
    causal_link_type: DIRECT
  - target: Seizure
    description: >-
      Leigh-like HIBCH disease can present with seizures in neonatal and
      infantile-onset disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41264763
      reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Infantile onset is the most common phenotype, presenting in the first
        two years of life with feeding difficulties, vomiting, developmental
        delay with regression, hypotonia, seizures, movement disorder,
        microcephaly, vision impairment, and episodes of neurologic
        deterioration.
      explanation: >-
        GeneReviews supports seizures as part of the infantile Leigh-like HIBCH
        neurologic presentation.
  - target: Dystonia
    description: >-
      Later-onset HIBCH neurodegeneration can include paroxysmal dystonia as
      part of the movement-disorder phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41264763
      reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Late onset is the second most common phenotype, presenting in childhood
        as a slowly progressive disease with significant movement disorder with
        or without paroxysmal dystonia, variable cognitive impairment, and high
        survivability.
      explanation: >-
        GeneReviews supports paroxysmal dystonia within the later-onset HIBCH
        movement-disorder phenotype.
  - target: Microcephaly
    description: >-
      Infantile-onset HIBCH deficiency can include microcephaly as part of the
      neurodevelopmental disease spectrum.
    causal_link_type: DIRECT
  - target: Visual impairment
    description: >-
      Leigh-like HIBCH neurodegeneration can include visual impairment.
    causal_link_type: DIRECT
  - target: Cognitive impairment
    description: >-
      Late-onset HIBCH deficiency can include variable cognitive impairment.
    causal_link_type: DIRECT
phenotypes:
- name: Global developmental delay
  category: Neurologic
  description: >-
    Affected children often present with developmental delay in early life.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties.
    explanation: >-
      This directly supports developmental delay as a prominent HIBCH
      phenotype.
- name: Developmental regression
  category: Neurologic
  description: >-
    Loss of previously acquired developmental skills is a common early
    manifestation of HIBCH deficiency.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties.
    explanation: >-
      This directly supports developmental regression as a prominent HIBCH
      phenotype.
- name: Hypotonia
  category: Neurologic
  description: >-
    Low tone is a prominent early neurologic feature in HIBCH deficiency.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties.
    explanation: >-
      This directly supports hypotonia as a common HIBCH presentation.
- name: Encephalopathy
  category: Neurologic
  description: >-
    Leigh-like encephalopathy reflects the central nervous system involvement
    of HIBCH deficiency.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties.
    explanation: >-
      This directly supports encephalopathy as part of the HIBCH phenotype.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Infants with HIBCH deficiency often have poor feeding in the setting of
    early neurodegenerative disease.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical manifestations were developmental regression/delay,
      hypotonia, encephalopathy, and feeding difficulties.
    explanation: >-
      This directly supports feeding difficulties as a core clinical feature.
- name: Vomiting
  category: Gastrointestinal
  subtype: Infantile onset
  description: >-
    Vomiting is a feature of infantile-onset HIBCH deficiency, the most common
    disease subtype.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infantile onset is the most common phenotype, presenting in the first two
      years of life with feeding difficulties, vomiting, developmental delay
      with regression, hypotonia, seizures, movement disorder, microcephaly,
      vision impairment, and episodes of neurologic deterioration.
    explanation: >-
      GeneReviews documents vomiting as a feature of infantile-onset HIBCH
      deficiency.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures occur in neonatal and infantile-onset HIBCH deficiency and may
    accompany Leigh-like neurodegeneration.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neonatal onset, the least frequent phenotype, is characterized by hypotonia,
      seizures, and feeding difficulties at birth.
    explanation: >-
      This directly supports seizures as part of the HIBCH clinical spectrum.
- name: Movement disorder
  category: Neurologic
  description: >-
    Later-onset HIBCH deficiency can present with a progressive movement
    disorder, sometimes with paroxysmal dystonia.
  phenotype_term:
    preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late onset is the second most common phenotype, presenting in childhood as
      a slowly progressive disease with significant movement disorder with or
      without paroxysmal dystonia, variable cognitive impairment, and high
      survivability.
    explanation: >-
      This directly supports a movement disorder phenotype in the HIBCH spectrum.
- name: Dystonia
  category: Neurologic
  description: >-
    Paroxysmal dystonia can accompany the movement-disorder phenotype in late
    onset HIBCH deficiency.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late onset is the second most common phenotype, presenting in childhood as
      a slowly progressive disease with significant movement disorder with or
      without paroxysmal dystonia, variable cognitive impairment, and high
      survivability.
    explanation: >-
      This directly supports dystonia as part of the late-onset HIBCH spectrum.
- name: Microcephaly
  category: Neurologic
  subtype: Infantile onset
  description: >-
    Microcephaly is reported in infantile-onset HIBCH deficiency.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infantile onset is the most common phenotype, presenting in the first two
      years of life with feeding difficulties, vomiting, developmental delay
      with regression, hypotonia, seizures, movement disorder, microcephaly,
      vision impairment, and episodes of neurologic deterioration.
    explanation: >-
      GeneReviews documents microcephaly as a feature of infantile-onset HIBCH
      deficiency.
- name: Visual impairment
  category: Ophthalmologic
  subtype: Infantile onset
  description: >-
    Visual impairment is reported in infantile-onset HIBCH deficiency and is
    managed with ophthalmology assessment and low vision services.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infantile onset is the most common phenotype, presenting in the first two
      years of life with feeding difficulties, vomiting, developmental delay
      with regression, hypotonia, seizures, movement disorder, microcephaly,
      vision impairment, and episodes of neurologic deterioration.
    explanation: >-
      GeneReviews documents vision impairment as a feature of infantile-onset
      HIBCH deficiency.
- name: Cognitive impairment
  category: Neurologic
  subtype: Late onset
  description: >-
    Variable cognitive impairment can occur in the late-onset HIBCH phenotype.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late onset is the second most common phenotype, presenting in childhood as
      a slowly progressive disease with significant movement disorder with or
      without paroxysmal dystonia, variable cognitive impairment, and high
      survivability.
    explanation: >-
      GeneReviews documents variable cognitive impairment in late-onset HIBCH
      deficiency.
biochemical:
- name: C4-OH acylcarnitine
  presence: INCREASED
  context: >-
    Elevation of hydroxy-C4-carnitine in dried blood spots is a useful
    biochemical clue in HIBCH deficiency.
  readouts:
  - target: Valine catabolic block
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated C4-OH acylcarnitine reports disturbed valine catabolism
      downstream of impaired HIBCH activity.
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five (5/7) patients presented with elevated C4-OH in dried blood spots,
      and the level was probably correlated with the NPMDS scores during the peak
      disease phase.
    explanation: >-
      This directly supports elevated C4-OH as a recurrent biochemical marker.
- name: Urinary 2,3-dihydroxy-2-methylbutyrate
  presence: INCREASED
  context: >-
    Urinary 2,3-dihydroxy-2-methylbutyrate is an elevated organic acid marker
    in HIBCH deficiency.
  readouts:
  - target: Valine catabolic block
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated urinary 2,3-dihydroxy-2-methylbutyrate reports accumulation of
      valine-derived intermediates from the HIBCH catabolic block.
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients
      and elevated S-(2-caboxypropyl)cysteamine in urine was found in three
      patients (3/3).
    explanation: >-
      This directly supports urinary 2,3-dihydroxy-2-methylbutyrate as a
      disease-associated biochemical marker.
- name: Urinary S-(2-carboxypropyl)cysteamine
  presence: INCREASED
  context: >-
    Urinary S-(2-carboxypropyl)cysteamine is another disease-associated
    metabolite in HIBCH deficiency.
  readouts:
  - target: Valine catabolic block
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated urinary S-(2-carboxypropyl)cysteamine reports toxic
      valine-derived intermediate buildup in HIBCH deficiency.
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients
      and elevated S-(2-caboxypropyl)cysteamine in urine was found in three
      patients (3/3).
    explanation: >-
      This directly supports urinary S-(2-carboxypropyl)cysteamine as a
      disease-associated biochemical marker.
genetic:
- name: HIBCH
  association: Loss of function
  gene_term:
    preferred_term: HIBCH
    term:
      id: hgnc:4908
      label: HIBCH
  evidence:
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HIBCH deficiency, a disorder of valine catabolism, is a novel cause of
      the multiple mitochondrial dysfunctions syndrome, and should be considered
      in the differential diagnosis of patients presenting with multiple RC
      deficiencies and/or pyruvate dehydrogenase deficiency.
    explanation: >-
      This directly supports HIBCH as the causal gene and explicitly names the
      relevant mitochondrial differential diagnosis context.
  - reference: CGGV:assertion_26621ace-7c6b-4a1c-8286-02c4cb8a1544-2019-11-07T222437.403Z
    reference_title: "HIBCH / 3-hydroxyisobutyryl-CoA hydrolase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HIBCH | HGNC:4908 | 3-hydroxyisobutyryl-CoA hydrolase deficiency | MONDO:0009603 | AR | Definitive"
    explanation: ClinGen classifies the HIBCH-3-hydroxyisobutyryl-CoA hydrolase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Molecular testing confirms the diagnosis by identifying biallelic
    pathogenic HIBCH variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: HIBCH
        term:
          id: hgnc:4908
          label: HIBCH
  results: Biallelic pathogenic HIBCH variants support the diagnosis.
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Applying next-generation sequencing, we identified eight patients with
      HIBCH mutations from our cohort of 181 cases of genetically diagnosed
      Leigh/Leigh-like syndrome.
    explanation: >-
      This directly supports molecular genetic testing as the confirmatory
      diagnostic approach.
- name: Brain MRI
  description: >-
    Brain magnetic resonance imaging helps identify Leigh-like basal ganglia
    abnormalities.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  results: Basal ganglia abnormalities and Leigh-like lesions support the diagnosis.
  evidence:
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two brothers born to distantly related Pakistani parents presenting in
      early infancy with a progressive neurodegenerative disorder, associated
      with basal ganglia changes on brain magnetic resonance imaging, were
      investigated for suspected Leigh-like mitochondrial disease.
    explanation: >-
      This directly supports MRI as an important diagnostic procedure and
      establishes the characteristic basal ganglia pattern.
differential_diagnoses:
- name: Leigh syndrome
  disease_term:
    preferred_term: Leigh syndrome
    term:
      id: MONDO:0009723
      label: Leigh syndrome
  description: >-
    HIBCH deficiency is a recognized Leigh-like disorder and can be mistaken
    for Leigh syndrome on clinical grounds.
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series
    explanation: >-
      This directly supports Leigh syndrome as an important clinical differential.
- name: Pyruvate dehydrogenase deficiency
  disease_term:
    preferred_term: pyruvate dehydrogenase deficiency
    term:
      id: MONDO:0019169
      label: pyruvate dehydrogenase deficiency
  description: >-
    Because HIBCH deficiency can produce pyruvate dehydrogenase complex
    dysfunction, primary PDH deficiency is a major differential diagnosis.
  evidence:
  - reference: PMID:24299452
    reference_title: "HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HIBCH deficiency, a disorder of valine catabolism, is a novel cause of
      the multiple mitochondrial dysfunctions syndrome, and should be considered
      in the differential diagnosis of patients presenting with multiple RC
      deficiencies and/or pyruvate dehydrogenase deficiency.
    explanation: >-
      This explicitly names pyruvate dehydrogenase deficiency as a key
      differential diagnosis.
- name: ECHS1 deficiency
  disease_term:
    preferred_term: mitochondrial short-chain Enoyl-CoA hydratase 1 deficiency
    term:
      id: MONDO:0014563
      label: mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
  description: >-
    ECHS1 deficiency is the key biochemical differential because ECHS1 acts
    immediately upstream of HIBCH in valine degradation and can present with a
    remarkably similar Leigh-like phenotype.
  evidence:
  - reference: PMID:37309295
    reference_title: "Acyl-CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA).
    explanation: >-
      This review explicitly places ECHS1 deficiency alongside HIBCH deficiency
      in the valine/isoleucine degradation disorders with overlapping biochemical
      context.
treatments:
- name: Valine-Restricted Diet
  description: >-
    Dietary restriction of valine is the primary targeted therapy for HIBCH
    deficiency, addressing the block in valine catabolism. Special medical
    food formulas can be delivered orally or by gastrostomy tube, with total
    protein restriction as an alternative when formula adherence is poor.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Valine catabolic block
    treatment_effect: MODULATES
    description: >-
      Valine restriction reduces dietary substrate flux into the impaired
      valine catabolic pathway.
    evidence:
    - reference: PMID:41264763
      reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MANAGEMENT: Targeted therapy: Valine-restricted diet.
      explanation: >-
        GeneReviews identifies valine restriction as targeted therapy for the
        pathway-level HIBCH defect.
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MANAGEMENT: Targeted therapy: Valine-restricted diet. As seen in other
      metabolic disorders, treatment using special formulas (medical food) can
      be implemented successfully via oral route in individuals diagnosed
      within the first few months of life.
    explanation: >-
      GeneReviews explicitly identifies valine-restricted diet as the primary
      targeted therapy for HIBCH deficiency.
- name: Supportive metabolic and dietary management
  description: >-
    HIBCH deficiency has no established curative therapy, but reported patients
    have received drug and dietary management with clinical improvement in some
    cases.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:33762937
    reference_title: "Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We administered drug and dietary treatment. During follow-up, five
      patients responded positively to treatment with a significant decrease in
      NPMDS scores.
    explanation: >-
      This supports the use of non-curative supportive metabolic management,
      although the paper does not specify a standardized regimen.
- name: Agents and diets to avoid
  description: >-
    Due to secondary mitochondrial abnormalities in HIBCH deficiency, sodium
    valproate should be avoided when possible and ketogenic or modified Atkins
    diets should be avoided because of potential side effects.
  notes: >-
    GeneReviews also advises careful anesthesia use, avoiding prolonged propofol,
    preventing catabolism, avoiding neuromuscular blockers in those with muscle
    disease, avoiding lactate-containing agents, and avoiding triheptanoin and
    dichloroacetate.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:41264763
    reference_title: 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Due to secondary mitochondrial
      abnormalities it may be beneficial to avoid sodium valproate if possible;
      consider anesthesia use carefully; avoid prolonged propofol use; prevent
      catabolism; avoid neuromuscular blocking agents in those with muscle
      disease; avoid lactate-containing agents, including dialysate containing
      lactate; ketogenic / modified Atkins diets should be avoided due to
      potential side effects; triheptanoin is contraindicated due to the
      potential increase in propionyl-CoA; dichloroacetate, as there is no
      published evidence to support its use in HIBCH deficiency.
    explanation: >-
      GeneReviews explicitly lists valproate and ketogenic or modified Atkins
      diets among agents and circumstances to avoid in HIBCH deficiency.
clinical_trials: []
datasets: []
references:
- reference: PMID:41264763
  title: "3-Hydroxyisobutyryl-CoA Hydrolase Deficiency."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:41264763

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency.

No top-level findings curated for this source.

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 3-hydroxyisobutyryl-CoA hydrolase deficiency. Core disease mechanisms, mol...

Asta Scientific Corpus Retrieval 20 citations 2026-04-15T19:37:45.204012

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 3-hydroxyisobutyryl-CoA hydrolase deficiency. Core disease mechanisms, mol...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.486) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[2] Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm

Authors: F. R. Danti, F. Invernizzi, I. Moroni, B. Garavaglia, N. Nardocci et al.
Year: 2021
Venue: Frontiers in Neurology
URL: https://www.semanticscholar.org/paper/92b36a8a32d63b0a6cb99345cd885e3a6018171c
DOI: 10.3389/fneur.2021.658178
PMID: 34140924
PMCID: 8203909
Citations: 4
Summary: The clinical, genetic, pathophysiologic, and therapeutic landscape of paroxysmal exercise induced neurological symptoms is reviewed, focusing on phenomenology and differential diagnosis.
Evidence snippets:
Snippet 1 (score: 0.482) > PED has been recently associated with the deficiency of a number of mitochondrial enzymes involved in energy production and branched-chain amino acids (BCAA; leucine, isoleucine, and valine) catabolism. They include Pyruvate dehydrogenase (PDH) complex, short-chain enoyl-CoA hydratase (ECSH1) and 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) (Figure 2) (33, 34). > PDH complex catalyses the oxidative decarboxylation of pyruvate with the production of acetyl-CoA; therefore, it connects the glycolytic pathway to the Krebs cycle and plays a central role in glucose metabolism in fed and fasting states. PDH complex is composed of three catalytic subunits: pyruvate dehydrogenase (PDH; E1, a heterotetramer of 2 subunits encoded by PDHA1 and PDHB1 genes), dihydrolipoamide acetyltransferase (E2, encoded by DLAT gene), and dihydrolipoamide dehydrogenase (E3, encoded by DLD gene), and of an additional component, the E3-binding protein (encoded by PDHX1) (35, 36). PDHA1, DLAT, and PDHX1 mutations have been linked to continuously expanding phenotypes inherited with X-linked (PDHA1 mutations, representing the main cause of PDH deficiency) or autosomal recessive pattern (DLAT and PDHX1 mutation). Clinical findings range from severe infantile lactic acidosis to milder chronic neurological disorders including intermittent and recurrent acute neurological symptoms such as episodic ataxia, peripheral weakness, and movement disorders such as PED and PNKD (36-38). In few patients recurrent dystonic or hemidystonic attacks have been described; they are triggered by prolonged walking and running and occur as a unique clinical manifestation or within complex neurological phenotypes (39-41).

[3] Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome

Authors: Junling Wang, Zhimei Liu, Manting Xu, Xiaodi Han, C. Ren et al.
Year: 2021
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/d344b1c2d00932f15f1b993fbd15d7852ed52b06
DOI: 10.3389/fphar.2021.605803
PMID: 33762937
PMCID: 7982470
Citations: 14
Influential citations: 3
Summary: The purpose of this study was to analyze the phenotypic spectrum, follow-up results, metabolites, and genotypes of patients with HIBCH deficiency presenting with Leigh/Leigh-like syndrome and explore specific metabolites related to disease diagnosis and prognosis through retrospective and longitudinal studies.
Evidence snippets:
Snippet 1 (score: 0.472) > 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH, NM_014362.3) gene mutation can cause HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series have investigated the relationship between metabolites and clinical phenotypes or the effects of treatment, although 34 patients with HIBCH mutations from 27 families have been reported. The purpose of this study was to analyze the phenotypic spectrum, follow-up results, metabolites, and genotypes of patients with HIBCH deficiency presenting with Leigh/Leigh-like syndrome and explore specific metabolites related to disease diagnosis and prognosis through retrospective and longitudinal studies. Applying next-generation sequencing, we identified eight patients with HIBCH mutations from our cohort of 181 cases of genetically diagnosed Leigh/Leigh-like syndrome. Six novel HIBCH mutations were identified: c.977T>G [p.Leu326Arg], c.1036G>T [p.Val346Phe], c.750+1G>A, c.810-2A>C, c.469C>T [p.Arg157], and c.236delC [p.Pro79Leufs5]. The Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) was employed to assess disease progression and clinical outcomes. The non-invasive approach of metabolite analysis showed that levels of some were associated with clinical phenotype severity. Five (5/7) patients presented with elevated C4-OH in dried blood spots, and the level was probably correlated with the NPMDS scores during the peak disease phase. 2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients and elevated S-(2-caboxypropyl)cysteamine in urine was found in three patients (3/3). The median age at initial presentation was 13 months (8–18 months), and the median follow-up was 2.3 years (range 1.3–7.2 years). We summarized and compared with all reported patients with HIBCH mutations. The most prominent clinical manifestations were developmental regression/

[4] Identification of HIBCH and MGME1 as Mitochondrial Dynamics‐Related Biomarkers in Alzheimer's Disease Via Integrated Bioinformatics Analysis

Authors: Hailong Li, Fei Feng, Shou-pin Xie, Yanping Ma, Yafeng Wang et al.
Year: 2025
Venue: IET Systems Biology
URL: https://www.semanticscholar.org/paper/77185e17e1f3375b9031c9851afadaced3eecc7a
DOI: 10.1049/syb2.70018
PMID: 40286336
PMCID: 12033025
Citations: 2
Summary: HIBCH and MGME1 are promising diagnostic biomarkers for AD with AUC values of 0.73 and 0.74 and Mechanistically, miR‐922 was experimentally validated to directly bind MGME1 3′UTR.
Evidence snippets:
Snippet 1 (score: 0.471) > In summary, MGME1 deficiency may impair mtDNA repair, leading to mitochondrial genome instability and bioenergetic failure. These findings collectively nominate MGME1 as a promising AD biomarker, with therapeutic targeting of MGME1 potentially mitigating pathological mtDNA-mediated neuroinflammation. The 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) enzyme, which is encoded by HIBCH, is involved in significant stages of valine degradation. Neurological symptoms resulting from uncommon metabolic dysfunctions are caused by HIBCH deficit (HIBCHD) [27]. An uncommon condition of the mitochondrial valine metabolism known as 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency can cause organic aciduria, motor delay, hypotonia, ataxia, dystonia, seizures, poor eating and developmental regression or delay [4]. Both HIBCH deficiency and Leigh/ Leigh-like illness are caused by mutations in the 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) gene [4]. Leighlike disease and HIBCH deficiency can be caused by mutations in the 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) gene [4]. Neuroimaging results show abnormalities in signals in the cerebral peduncles and globus pallidi, which are located in the deep grey matter [4]. The findings of neuroimaging reveal anomalies in signals within the deep grey matter, specifically in the cerebral peduncles and globus pallidi [28,29]. It was discovered that HIBCH is one of the proteins that is overexpressed in malignancies, such as ovarian tumours, and that is expressed differentially in mitochondria [30], Blocking 3hydroxyisobutyryl-CoA hydrolase (HIBCH) to stop the breakdown of valine resulted in decreased intracellular succinate, a decrease in the development of cancerous prostate cells, and impaired cellular respiration [31].

[5] HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase

Authors: S. Ferdinandusse, H. Waterham, S. Heales, Garry K. Brown, I. Hargreaves et al.
Year: 2013
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/54d1e94c64b6353cdcf9e97e451e68839e044cd0
DOI: 10.1186/1750-1172-8-188
PMID: 24299452
PMCID: 4222069
Citations: 80
Influential citations: 7
Summary: HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.
Evidence snippets:
Snippet 1 (score: 0.470) > Mitochondrial disorders affect approximately 1 in 5000 births, and are clinically, biochemically and genetically heterogeneous [1]. Combined deficiency of multiple respiratory chain (RC) enzymes is one of the most frequent findings in children with suspected mitochondrial disease, representing approximately 30% of cases in whom a biochemical abnormality is identified. Approximately 50% of patients with multiple RC deficiencies have impaired replication or maintenance of the mitochondrial DNA (mtDNA), leading to progressive depletion of mtDNA [2] or accumulation of multiple mtDNA deletions. The remaining~50% of cases have heterogeneous underlying causes, including mitochondrial or nuclear-encoded defects of mitochondrial protein synthesis [3] and the multiple mitochondrial dysfunctions syndrome, in which the activity of PDHc is also impaired [4][5][6]. Defects in mtDNA repair, maintenance or translation result in combined deficiency of complexes I, III and IV (i.e. complexes that contain mtDNA-encoded subunits) whereas the multiple mitochondrial dysfunctions syndrome usually affects complexes containing iron-sulphur (Fe-S) clusters (complexes I, II and III) as well as PDHc. > Neurological features of cerebral organic acidurias (disorders of degradation of the carbon skeleton of amino acids) can be clinically and radiologically indistinguishable from mitochondrial encephalomyopathies caused by primary RC deficiencies; seizures, neurological regression and bilateral symmetrical basal ganglia lesions may occur in both groups of disorders [7][8][9][10]. 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) is a mitochondrial enzyme that catalyses the fifth step of valine catabolism, the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxyisobutyrate ( Figure 1a). HIBCH deficiency has previously been reported in only two patients [11,12]. We now describe two new genetically confirmed cases (siblings), one of whom presented with combined defects of multiple RC enzymes and the pyruvate dehydrogenase complex (PDHc). This potentially represents a new disease mechanism mimicking the multiple mitochondrial dysfunctions syndrome, namely degradation of multiple enzymes resulting from accumulation of a toxic metabolite methacrylyl

[6] Current and Emerging Issues in Familial Hypobetalipoproteinemia-related Steatotic Liver Diseases

Authors: Tian-Wen Lou, Tian-Yi Ren, Jian-gao Fan
Year: 2025
Venue: Journal of Clinical and Translational Hepatology
URL: https://www.semanticscholar.org/paper/cf1c6534ba154bbb870b421a4e111acb62023405
DOI: 10.14218/JCTH.2025.00360
PMID: 41473260
PMCID: 12745358
Summary: Challenges include insufficient diagnosis, sparse epidemiological data, and unclear disease progression; enhanced genetic testing, mechanistic research, and longitudinal studies are critical to improving diagnosis, risk assessment, and therapies for FHBL-associated liver disease.
Evidence snippets:
Snippet 1 (score: 0.454) > ecent advances in molecular genetics have refined our understanding of APOB-related pathophysiology, yet critical questions remain unanswered, particularly regarding why some FHBL patients develop progressive liver disease while others remain stable, and what the specific mechanisms and molecular pathways are for the occurrence and development of liver disease. > This review aims to refocus attention on the hepatic aspects of FHBL by (i) summarizing current knowledge of molecular genetics, (ii) analyzing the spectrum and progression of liver disease in affected individuals, (iii) exploring mechanistic hypotheses that may explain liver disease, and (iv) outlining the clinical treatment plan. We aim to establish FHBL not only as a disorder of lipid metabolism but also as a valuable window into the pathogenesis of steatotic liver disease.

[7] HMG–CoA Lyase Deficiency

Authors: B. Puisac, María Arnedo, M. Gil-Rodríguez, E. Teresa, Á. Pié et al.
Year: 2011
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/ffd0bf7b7af0c6b88ada7c59a737d4d83e10c3b2
DOI: 10.5772/20252
Citations: 4
Summary: A recent study of differential expression of human HL in liver, pancreas, testis, heart, skeletal muscle and brain that can help us to understand the consequences of this deficiency and draw a map of incidence.
Evidence snippets:
Snippet 1 (score: 0.449) > The HMG-CoA lyase (HL) deficiency or 3-hydroxy-3-methylglutaric aciduria (MIM 246450) is an inborn error of intermediary metabolism that was first described in 1976 by Faull et al (Faull et al., 1976). Because its clinical manifestations, it has been included within the Sudden Infant Death Syndrome (Wilson et al., 1984). At present, it is considered a rare disease (<1/100,000 live neonates) that should be diagnosed at early age because there is a simple and effective treatment (Watson et al., 2006). HL is a mitochondrial enzyme that catalyzes the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, which is the common final step of ketogenesis and leucine catabolism (Figure 1). Patients with this disease suffer on the one hand, the absence of ketone bodies as alternative energy source of glucose and on the other hand, the accumulation of toxic metabolites of leucine catabolism. The most frequently affected organs are the liver and the brain, but the pancreas and the heart can also be involved. This chapter discusses a recent study of differential expression of human HL in liver, pancreas, testis, heart, skeletal muscle and brain that can help us to understand the consequences of this deficiency (Puisac et al., 2010). It is an autosomal recessive disease caused by mutations in the HMGCL gene. The study of these mutations and patients origin helps to draw a map of incidence in which three countries stand out for their high frequency: Saudi Arabia (Ozand et al., 1992), Spain and Portugal (Menao et al., 2009). At present, the functional study of missense mutations is possible thanks to the knowledge of the structure (Fu et al., 2006) and mechanism of the enzyme (Fu et al., 2010) and also by the development of a method of simple and efficient expression of the protein (Menao et al., 2009). Finally, despite the current knowledge of the disease, genotype-phenotype correlations are difficult to establish.

[8] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
Year: 2024
Venue: Metabolites
URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
DOI: 10.3390/metabo14100515
PMID: 39452896
PMCID: 11509386
Citations: 2
Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
Evidence snippets:
Snippet 1 (score: 0.444) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[9] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.436) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[10] Short-chain enoyl-CoA hydratase deficiency causes prominent ketoacidosis with normal plasma lactate levels: A case report

Authors: Madoka Uesugi, Jun Mori, S. Fukuhara, N. Fujii, Tadaki Omae et al.
Year: 2020
Venue: Molecular Genetics and Metabolism Reports
URL: https://www.semanticscholar.org/paper/872b6da3f3bccf1ecdc81939f3fa8209fb3263c4
DOI: 10.1016/j.ymgmr.2020.100672
PMID: 33163364
PMCID: 7606867
Citations: 8
Influential citations: 1
Summary: A 7-month-old boy with Short-chain enoyl-CoA hydratase (ECHS1) deficiency concomitant with prominent ketoacidosis, and no elevation in plasma lactate levels is reported, expanding the understanding of the multiple symptoms of ECHS1 deficiency and emphasizing the importance of genetic testing for inborn errors of metabolism to initiate early treatment.
Evidence snippets:
Snippet 1 (score: 0.431) > ECHS1 is a mitochondrial enzyme that catalyzes reactions in multiple metabolic pathways, such as fatty acid ß oxidation and degradation of branched-chain amino acids (valine, leucine, and isoleucine). ECHS1 deficiency was first reported in Leigh syndrome by Peters in 2014 [1]. Since then, ~50 cases of ECHS1 deficiency have been reported. The symptoms and findings of ECHS1 deficiency vary and the frequency of ECHS1 deficiency is rare. Even patients with identical genotypes have different symptoms. The main pathophysiology of ECHS1 deficiency involves the accumulation of toxic intermediate metabolites, such as methacrylyl-CoA, in the mitochondria in the valine catabolic pathway. Patients with ECHS1 deficiency have characteristic symptoms, such as severely delayed psychomotor development, nystagmus, hyperlactatemia, and brain lesions in the basal ganglia, with metabolic acidosis and variable ketosis. This case report is based on a 7-month-old boy with ECHS1 deficiency and chief complaints of conjugate deviation and hypotonia. The findings upon examination of the patient were: 1) remarkable ketoacidosis and 2) normal levels of lactate in the blood and cerebrospinal fluid. > The 3-hydroxyisobutyryl-CoA hydrolase gene (HIBCH) is located downstream of ECHS1 in the valine metabolic pathway. Thus, patients with ECHS1 deficiency show symptoms similar to those in patients with a deficiency of HIBCH. Patients with HIBCH deficiency exhibit marked ketoacidosis during stress conditions, such as fever. This can be attributed to the enhanced supply of ATP to the brain owing to fatty acid ß oxidation. In contrast, ketoacidosis is not always observed with patients with ECHS1 deficiency. Some patients with ECHS1 deficiency have ketoacidosis [4], but some patients with ECHS1 deficiency do not present with prominent ketoacidosis due to the impairment of short-chain fatty acid β oxidation and inability to produce ketone bodies [5]. It has recently been reported that ECHS1 is less involved in isoleucine metabolism and fatty acid ß oxidation [7].

[11] Frontiers in metabolic physiology grand challenges

Authors: J. Imig
Year: 2022
Venue: Frontiers in Physiology
URL: https://www.semanticscholar.org/paper/19e2780d459288513f034516e0a7d5fa4e12298f
DOI: 10.3389/fphys.2022.879617
PMID: 36035475
PMCID: 9399398
Citations: 1
Summary: In this chapter seven subsequent studies of the determinants of infectious disease in eight operation rooms were studied.
Evidence snippets:
Snippet 1 (score: 0.430) > Research in this area will identify novel therapeutic targets for diabetic complications at the levels of transcription and translation, protein expression and activity, and cell and organ levels. Major challenges in diabetes include defining molecular mechanisms and pathways implicated in insulin metabolism, evaluating transcriptomics of high glucose on different cell types, defining the contribution of the innate immune response and NLRP3 inflammasome, understanding metabolic mechanisms that drive beta cell dysfunction, and defining metabolic processes in key insulin-target tissues. > NAFLD is a rapidly growing public health concern that occurs in 25% of the world population and is driven in large part by the obesity and type 2 diabetes epidemic (Caussy et al., 2021;Targher et al., 2021). Intriguingly, NAFLD can be as high as 75% in diabetic patients (Caussy et al., 2021;Targher et al., 2021). Non-alcoholic steatosis (NASH) is a type of NAFLD that is associated with inflammation and hepatocyte lipotoxicity which leads to liver fibrosis and cancer (Caussy et al., 2021;Targher et al., 2021). NASH is expected to become the leading cause for liver transplantation in the next decade (Nephew and Serper, 2021). Mechanisms that contribute to NAFLD and progression to NASH include regulation of de novo lipogenesis by acetyl-CoA carboxylase, regulation of bile acid signaling by farnesoid X receptor (FXR), or oxidative stress induced fibrogenesis and inflammation by apoptosis signal-regulating kinase 1 (ASK1) (Attia et al., 2021;Koo and Han, 2021). Although often associated with obesity and diabetes, understanding pathophysiological mechanisms at the cellular hepatocyte and organ liver levels that result in NAFLD and progression to NASH will be key to developing therapeutics. > Major challenges to the epidemic of metabolic diseases are the focus of several publications in Frontiers in Metabolic Physiology. Studies in mice with type 2 diabetes have revealed metabolites involved in diabetic kidney disease.

[12] Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease

Authors: Martin Grønbæk-Thygesen, R. Hartmann-Petersen
Year: 2024
Venue: Cell & Bioscience
URL: https://www.semanticscholar.org/paper/d2dfbaee9666d4b1f681d466dae63d5a770fd34a
DOI: 10.1186/s13578-024-01224-6
PMID: 38582917
PMCID: 10998430
Citations: 7
Summary: The importance of high-throughput technologies and computational prediction tools for making genotype–phenotype predictions as they await the results of ongoing trials with gene therapy for Canavan disease is highlighted.
Evidence snippets:
Snippet 1 (score: 0.424) > Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype–phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease.

[13] iPSC‐Derived Liver Organoids as a Tool to Study Medium Chain Acyl‐CoA Dehydrogenase Deficiency

Authors: L. A. Kiyuna, José M. Horcas-Nieto, Christoff Odendaal, Miriam Langelaar-Makkinje, A. Gerding et al.
Year: 2025
Venue: Journal of Inherited Metabolic Disease
URL: https://www.semanticscholar.org/paper/547bf305207cfd00da79f778ed7ea7eb255f1018
DOI: 10.1002/jimd.70028
PMID: 40199742
PMCID: 11978564
Citations: 2
Summary: iPSC‐derived organoids of MCADD patients recapitulated the major biochemical phenotype of the disease, and this patient‐specific hepatic organoid system is a promising platform to study the phenotypic heterogeneity between MCADD patients.
Evidence snippets:
Snippet 1 (score: 0.423) > Medium chain acyl‐CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disease, characterized by biallelic variants in the ACADM gene. Interestingly, even with the same genotype, patients often present with very heterogeneous symptoms, ranging from fully asymptomatic to life‐threatening hypoketotic hypoglycemia. The mechanisms underlying this heterogeneity remain unclear. Therefore, there is a need for in vitro models of MCADD that recapitulate the clinical phenotype as a tool to study the pathophysiology of the disease. Fibroblasts of control and symptomatic MCADD patients with the c.985A>G (p.K329E) were reprogrammed into induced pluripotent stem cells (iPSCs). iPSCs were then differentiated into hepatic expandable organoids (EHOs), further matured to Mat‐EHOs, and functionally characterized. EHOs and Mat‐EHOs performed typical hepatic metabolic functions, such as albumin and urea production. The organoids metabolized fatty acids, as confirmed by acyl‐carnitine profiling and high‐resolution respirometry. MCAD protein was fully ablated in MCADD organoids, in agreement with the instability of the mutated MCAD protein. MCADD organoids accumulated medium‐chain acyl‐carnitines, with a strongly elevated C8/C10 ratio, characteristic of the biochemical phenotype of the disease. Notably, C2 and C14 acyl‐carnitines were found decreased in MCADD Mat‐EHOs. Finally, MCADD organoids exhibited differential expression of genes involved in ω‐oxidation, mitochondrial β‐oxidation, TCA cycle, and peroxisomal coenzyme A metabolism, particularly upregulation of NUDT7. iPSC‐derived organoids of MCADD patients recapitulated the major biochemical phenotype of the disease. Mat‐EHOs expressed relevant pathways involved in putative compensatory mechanisms, notably CoA metabolism and the TCA cycle. The upregulation of NUDT7 expression may play a role in preventing excessive accumulation of dicarboxylic acids

[14] Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

Authors: Christiana C. Christodoulou, M. Zachariou, Marios Tomazou, E. Karatzas, C. Demetriou et al.
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/04a48e68a0a0ad9eca22aeffdb8c22c7fb41ed86
DOI: 10.3390/ijms21197414
PMID: 33049985
PMCID: 7582902
Citations: 26
Influential citations: 2
Summary: The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset.
Evidence snippets:
Snippet 1 (score: 0.423) > HD is a monogenetic and incurable disease and at the same time its molecular manifestations remain highly complex and involve multiple cellular processes, genes, and metabolites, which needs to be investigated to understand HD pathology. Systems bioinformatics (SB) allows the integration of different biological omics data to better understand the biological pathways, mechanisms, genes and metabolites involved in HD and lead to possible therapeutic treatments and biomarker discovery. > SB is an interdisciplinary field which combines the research fields of systems biology and bioinformatics. SB allows the integration of biological data across the omics categories such a genomics, transcriptomics, proteomics, metabolomics, lipidomics, epigenomics and several types of omics data [7]. > A major approach in this direction is the generation and construction of biological networks representing each level of omics data and their integration in a layered network that permits the exchange of information between and within the layers. The goal is to reveal synergistic relationships among numerous factors rather than explore each entity individually. This data integration approach results in the construction of highly complex molecular interaction networks. The biological data, obtained through large-scale omics analysis can provide a better understanding into biological mechanisms and pathways and how a dysfunction in these mechanisms and pathways can cause the disease [7]. Furthermore, the emerging importance of biological network-based approaches, allows for potential biological and clinical applications by suggesting an intuitive and trustworthy approach to explore the biological and molecular complexity of a disease of interest [8]. > The metabolome is defined as the complete set of small chemical molecules found within a biological samples (urine, cerebrospinal fluid (CSF), serum, plasma), tissues and cells. Changes and interactions in gene and protein expression and the environment are directly revealed in the metabolome making it more chemically and physically complex than the genome, transcriptome and proteome. Metabolites are affected by the upstream influence of the genome, proteome, environmental and lifestyle factors, as well as medication and underlying diseases [9]. > Metabolomics is an omics category focused in the study of metabolites. Metabolites are defined as small biological and low molecular weight (<1500 Da) compounds, they are the end-products of metabolism [10].

[15] Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders

Authors: H. Stranneheim, A. Wedell
Year: 2016
Venue: Journal of Internal Medicine
URL: https://www.semanticscholar.org/paper/112c148c6b98b6d169cd0b67d258f97d4a225a8d
DOI: 10.1111/joim.12399
PMID: 26250718
Citations: 92
Influential citations: 3
Summary: Not only can rapid and safe diagnostics of virtually all known single‐gene defects now be established, but novel causes of disease in previously unsolved cases can also be identified, illuminating novel pathways important for normal physiology.
Evidence snippets:
Snippet 1 (score: 0.422) > Deficiency of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) is a rare defect in the valine catabolic pathway associated with severe brain damage (Leigh-like disease). Mutations in the HIBCH gene were excluded in patients with a remarkably similar biochemical and clinical phenotype. Exome sequencing instead identified mutations in the ECHS1 gene-encoding short-chain enoyl-CoA hydratase. This mitochondrial enzyme is active immediately upstream of HIBCH in the valine degradation pathway [30]. > A subgroup amongst IEMs is the mitochondrial disorders, resulting from impaired oxidative phosphorylation. These disorders affect at least 1 in 5000 live births [31] and can be caused by mutations in nuclear genes or in mitochondrial DNA (mtDNA). The small, circular mtDNA molecule encodes 13 components of the respiratory chain as well as two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs) required for the mitochondrial translational machinery. The majority of the subunits of the respiratory chain as well as factors required for maintenance and expression of mtDNA, including replication, transcription and translation, are encoded by nuclear DNA genes (Fig. 2). Mitochondrial function thus depends critically on the coordinated expression of genes from two genomes. Around 100 mostly recessive nuclear genes are currently known to cause mitochondrial disorders, and the number is increasing rapidly due in large part to exome sequencing. > One approach to facilitating the discovery of novel disease genes causing mitochondrial disorders relied on specifically targeting the mitochondrial genome together with all coding exons of the approximately 1000 nuclear genes known to be located inside the mitochondria in patients with biochemical evidence of impaired mitochondrial function [32]. More important, however, is the possibility of directly combining biochemical and genetic investigations. Detailed characterization of mitochondrial respiratory chain function in cells or tissue from affected patients can locate defects such as in the synthesis or assembly of specific enzyme complexes required for oxidative phosphorylation, providing a functional framework to aid the identification and validation of pathogenic variants. For example, when mutations in NDUFB3, encoding a subunit of complex I, were identified in a patient with severe, early lethal mitochondrial disease due to complex I deficiency, these could indeed be considered pathogenic even though mutations in this gene had not previously been reported

[16] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.422) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[17] [Retracted] Identification of HIBCH as a Fatty Acid Metabolism‐Related Biomarker in Aortic Valve Calcification Using Bioinformatics

Authors: Jun-Yu Chen, Ya-Ru Sun, Tao Xiong, Guan-nan Wang, Qing Chang
Year: 2022
Venue: Oxidative Medicine and Cellular Longevity
URL: https://www.semanticscholar.org/paper/8d3a50a11e93a0e40c20eac1e66ea3b47476e3e1
DOI: 10.1155/2022/9558713
Citations: 1
Summary: 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) was a biomarker of fatty acid metabolism‐related genes in AVC and could be applied as a diagnostic marker for AVC.
Evidence snippets:
Snippet 1 (score: 0.419) > The results showed a significant association between HIBCH and various immune cells. This suggests that HIBCH in AVC tissues might impact the Oxidative Medicine and Cellular Longevity progression of AVC by affecting immune cells. The GSEA results provide additional evidence that HIBCH may act through immune-related pathways. HIBCH (3-hydroxyisobutyryl-CoA hydrolase) is an enzyme that catalyzes the conversion of 3-hydroxyisobutyryl-CoA to 3-hydroxyisobutyric acid [27]. It is a key mitochondrial protein required for valine catabolism [28,29]. The metabolite 3-hydroxyisobutyric acid is transformed further to succinyl coenzyme A which is involved in the metabolism of the tricarboxylic acid (TCA) cycle. A prior research has reported the involvement of HIBCH in hepatic mitochondrial fatty acid oxidation [30]. Various studies have shown that HIBCH is related to colorectal cancer [31], ovarian cancer [32,33], prostate cancer [34], paroxysmal dyskinesia [35], and Leigh syndrome [36][37][38][39]. In addition, a study also showed the association between HIBCH with AVC [40]. > With the advancement in the understanding of AVC, various researches have demonstrated the effect of immune cells in AVC. Previous studies have shown that both antigen-presenting cells (APCs) and macrophages exist in normal and pathologic valves, but the existence of T lymphocytes is characteristic of both aging and pathologic valves [41,42]. This lymphocytic infiltration is accompanied by increased neointima formation and osteogenesis, which is the hallmark and pathological signs of AVC [43]. The abundance of B lymphocytes in the valves is related to increased disease severity. In addition, prior researches showed that the depletion of natural killer T (NKT) cells can lead to improvement or worsening of a variety of fibrotic diseases [44][45][46].

[18] Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

Authors: Nagwa Gaboon, B. Banaganapalli, K. Nasser, M. Razeeth, Mosab S. Alsaedi et al.
Year: 2019
Venue: Saudi Journal of Biological Sciences
URL: https://www.semanticscholar.org/paper/f1f1341fd61e31f39a5129e7c80ff67cd0b6fb0f
DOI: 10.1016/j.sjbs.2019.10.001
PMID: 31889854
PMCID: 6933272
Citations: 17
Influential citations: 1
Summary: Genetic defects in RMND1 gene alters the mitochondrial energy metabolism leading to the accumulation of ceramide, and subsequently promote dysregulated apoptosis and tissue necrosis in kidneys, this study suggests.
Evidence snippets:
Snippet 1 (score: 0.416) > One of the recently identified nuclear genes involved in mitochondrial respiratory chain deficiencies is RMND1 (Required for Meiotic Nuclear Division protein 1) (Garcia-Diaz et al., 2012;Janer et al., 2012). It has been demonstrated that various novel and common recessive mutations in RMND1 are associated with multiple phenotypes characterized by delayed maturation of vision, developmental delay, dilated cardiomyopathy, deafness and neurological defects (Gupta et al., 2016), renal tubular acidosis type 4 presented as hyponatraemia and hyperkalaemia and cystic/hypoplastic kidneys (Ng et al., 2016). Likewise, complex clinical spectrum of patients with RMND1 mutations is emerging with infantile encephalomyopathy with lactic acidosis (Garcia-Diaz et al., 2012;Casey et al., 2016) to a less severe form of developmental delay, hypotonia, renal disease and congenital sensorineural deafness (Janer et al., 2015). Therefore, molecular screening of RMND1 gene will help identify the inheritance mode of causative genetic mutations in patients with renal and or neurological defects. > MIDs have complex etiologies with underlying cross talk of inter and intra molecular signaling. Hence, metabolomic studies on these patients could provide a better understanding of the interconnectivity between genetic and molecular networks (Davies, 2018). Metabolomic profiling examines the metabolic changes in body fluids driven from cellular processes to understand the onset and pathogenesis of disease phenotype (Abbiss et al., 2019). Metabolomics analyzes metabolites by either targeted or untargeted approaches. The untargeted approach involves hypothesis free surveying of hundreds of thousands of small molecule metabolites for discovering novel mechanisms or pathways, whereas the targeted one refers to measuring predefined sets of metabolites, typically focusing on a few pathways of interest (Kalim and Rhee, 2017). The specific relationship between inherited mutations in mitochondrial proteins and their functional impacts in terms of metabolic defects in chronic kidney disease (CKD) is not yet well characterized.

[19] Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence

Authors: Marilena Briglia, Fabio Allia, R. Avola, C. Signorini, V. Cardile et al.
Year: 2024
Venue: Nutrients
URL: https://www.semanticscholar.org/paper/7308e8ab8a771741ed66510938d52004f1d64f92
DOI: 10.3390/nu16183114
PMID: 39339713
PMCID: 11435074
Citations: 5
Influential citations: 1
Summary: This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors.
Evidence snippets:
Snippet 1 (score: 0.414) > The relationship between nutritional intervention and rare neurological diseases is an emerging area of research that may help to manage symptoms, slow disease progression, or even impact the underlying mechanisms of certain rare neurological disorders. The complex interactions between diet and neurological health require closer interdisciplinary collaboration between neurologists, dietitians, and researchers. It is crucial to conduct clinical trials to establish evidence-based dietary guidelines tailored to these unique conditions. > The major limits of this study reside in (i) the limited availability of data as accessed by the reduced number of published papers and completed clinical trials; (ii) the wide variety of the disease's pathophysiology; and (iii) the underestimated influence of individual variability due to genetic differences. Specifically, as reported above, the number of published articles about the role of diet/nutrients on rare neurological disorders is very small. Clinical data often derive from case reports or small cohort studies, and large-scale clinical trials are scarce due to the rarity of these disorders and the huge heterogeneity of clinical manifestations. Moreover, even if preclinical studies give us more detailed information about the impact of a specific nutrient on cell function or on disease progression in animal models, they could not reflect the patients' individual genetic differences and their global health status (e.g., integrity of anatomic structure and physiological functions as blood circulation, pressure, constipation, and deglutition). These latter aspects may influence how patients assume, metabolize, and distribute nutrients as has been discussed above in the case of cholesterol supplementation for Pelizaeus-Merzbacher disease. > Moreover, when searching for dietary recommendations for a specific rare disease, a great limit is the heterogeneity of occurring genetic mutations that turn into different phenotypes and clinical manifestations. Briefly, what could work for one patient may not be effective for another one, as enlightened here by reviewing the activity of trihydroxyisoflavone as a GALC-addressed chaperone. > However, despite these limitations, our analysis has, as a strength, the identification of a specific dietary intervention for the management of some symptoms. It is the case of ketogenic diet efficacy in different rare neurological diseases that share epilepsy in clinical manifestation.

[20] HMG-CoA Lyase Deficiency: A Retrospective Study of 62 Saudi Patients

Authors: M. Alfadhel, Basma Abadel, Hind Almaghthawi, Muhammad Umair, Z. Rahbeeni et al.
Year: 2022
Venue: Frontiers in Genetics
URL: https://www.semanticscholar.org/paper/080356c04b117156bf7674f3ee445870810ce7d0
DOI: 10.3389/fgene.2022.880464
PMID: 35646072
PMCID: 9136170
Citations: 17
Influential citations: 1
Summary: This is the largest cohort of HMGCLD patients reported from Saudi Arabia, signifying this disorder as a likely life-threatening disease, with a high prevalence in the region, and suggest that diagnosis at an early stage with careful dietary management may avoid metabolic crises.
Evidence snippets:
Snippet 1 (score: 0.409) > Therefore, the first step in the diagnosis is the MS/MS-based acylcarnitine profiling in dried blood spots/ plasma and the GC/MS-based organic acid analysis in urine. Then, molecular diagnosis using next-generation sequencing should be followed to pinpoint precisely the genetic cause of the disease (Ismail et al., 2019;Alfadhel et al., 2021). Similarly, targeted newborn screening should also be initiated to eradicate this severe disorder (Alfadhel et al., 2019). Similarly, Reimão et al. described late-onset diseases where a 29-year-old man with no prior medical history presented sudden coma, profound hypoglycemia, hyperammonemia, and metabolic acidosis without ketosis (Reimão et al., 2009). A 36-year-old woman with a late onset of an acute episode of hyperproteinorachia (0.73 g/L), hypoglycemia, and generalized seizures has also been reported (Bischof et al., 2004). Patients showing different levels of severity in the phenotypic presentation highlight clinical heterogeneity of the disorder. Still, it is difficult to establish a proper genotype-phenotype correlation in HMGCLD (Grunert et al., 2017;Alfadhel et al., 2017). > The mechanism of neurological pathophysiology in HGMCLD is still poorly understood; however, possible mechanisms include secondary carnitine deficiency, hypoketotic hypoglycemia, and intracellular toxic organic acid accumulation (Puisac et al., 2010). Furthermore, MRI shows a unique combination of T2-weighted diffuse mild signal changes with multiple foci of a more severe signal abnormality (Legault et al., 2015). Studies using rats revealed that the accumulation of the metabolite in HMGCLD results in oxidative stress in the developing rat's striatum that disrupts bioenergetics dynamics, signaling pathways, and ER-mitochondria communication, which might explain the HMGCLD disease pathogenesis (da Rosa et al., 2015).

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[17] [Retracted] Identification of HIBCH as a Fatty Acid Metabolism‐Related Biomarker in Aortic Valve Calcification Using Bioinformatics

[18] Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

[19] Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence

[20] HMG-CoA Lyase Deficiency: A Retrospective Study of 62 Saudi Patients

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